To further characterize the function of myostatin, in vivo metabolic assays were performed including euglycemic-hyperinsulinemic clamp studies, lipid oxidation and indirect calorimetry using wild type and myostatin null mice. We have also measured the effects of high fat and normal diets on insulin and glucose tolerance and the effects of exercise on myostatin mull mice as compared to wild type mice. We have found that myostatin null mice have improved insulin sensitivity and are resistant to weight gain and the development of insulin resistance when placed on a high-fat diet. Mice with muscle-specific inhibition of myostatin signaling due to over-expression of a dominant negative activin type IIB receptor (Acvr2b) have a similar phenotype as myostatin null mice. These results show that the improved insulin sensitivity, reduction of adipose mass, and resistance to diet-induced obesity seen in myostatin null mice can be explained by the loss of myostatin on muscle alone.